NM_001130823.3:c.1053A>G

Variant names:

• chr19-10160054-T-C
• rs139355567
• NM_001130823.3:c.1053A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001130823.3(DNMT1):​c.1053A>G​(p.Lys351Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000541 in 1,571,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.809
• Publications: 0 publications found

Genes affected

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNMT1 Gene-Disease associations (from GenCC):

• autosomal dominant cerebellar ataxia, deafness and narcolepsy

  Inheritance: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-10160054-T-C is Benign according to our data. Variant chr19-10160054-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 381073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.
• BS2: High AC in GnomAd4 at 9 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.1053A>G	p.Lys351Lys	synonymous	Exon 15 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.1005A>G	p.Lys335Lys	synonymous	Exon 14 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.1005A>G	p.Lys335Lys	synonymous	Exon 14 of 40	NP_001370.1	P26358-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.1053A>G	p.Lys351Lys	synonymous	Exon 15 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.1005A>G	p.Lys335Lys	synonymous	Exon 14 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.231A>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.0000816 AC: 9 AN: 110232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000126

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000525 AC: 13 AN: 247722 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461686 Hom.: 1 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000665 AC: 74 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000816 AC: 9 AN: 110232 Hom.: 0 Cov.: 33 AF XY: 0.0000376 AC XY: 2 AN XY: 53132

African (AFR) AF: 0.0000859 AC: 2 AN: 23296

American (AMR) AF: 0.00 AC: 0 AN: 11276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2844

East Asian (EAS) AF: 0.00 AC: 0 AN: 3612

South Asian (SAS) AF: 0.00 AC: 0 AN: 3196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.000126 AC: 7 AN: 55458

Other (OTH) AF: 0.00 AC: 0 AN: 1456

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DNMT1-related disorder (1)
-	-	1	Hereditary sensory neuropathy-deafness-dementia syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.35
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139355567; hg19: chr19-10270730;